Mitochondria are central key organelles to regulate a multitude of different metabolic and signaling pathways and also play an important role in programmed cell death ((McBride et al. (2006) Curr Biol. 16:R551; Graier et al. (2007) Eur J Physiol. 455, 375). The primary function of mitochondria is to produce ATP through the process of oxidative phosphorylation (OXPHOS), which is performed by the four respiratory complexes (complexes I-IV) and the ATP synthase (complex V), all located in the inner mitochondrial membrane (Saraste et al. (1999) Science, 283, 1488; Henze et al. (2003) Nature, 426, 127). In mitochondria superoxide (O2.−) is generated at several sites within the electron-transport chain (ETC), which is linked to bioenergetic function. However, faulty electron transfer at any point in the electron transport chain has a major impact on mitochondrial coupling (ATP synthesis) and production of reactive oxygen species (Murphy et al. (2009) Biochem J. 417, 1; Turrens et al. (2003) J Physiol. 552,335). Normally, mitochondria likely serve as a net sink rather than a net source of ROS (Mates et al. (1999) Clin Biochem. 32, 595; Gaetani et al. (1989) Blood. 73, 334). The cells have developed a number of efficient scavenger systems including antioxidant enzymes and the glutathione redox cycle with its associated constitutive enzymes as well as glutathione itself in the mitochondria and cytosol to cope with the normal production of reactive oxygen species. Superoxide is converted rapidly to hydrogen peroxide (H2O2) by spontaneous dismutation using superoxide dismutase (SOD) in the mitochondrial matrix (MnSOD) and the inter membrane space (IMS) and cytosol (CuZnSOD). Peroxidases and catalases also participate in the conversion of reactive oxygen species to water. The impaired oxidative phosphorylation function (OXPHOS) would lead to further production of ROS, which further overwhelms the endogenous antioxidant systems and exposing cellular macromolecules to oxidative damage. Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. The underlying biochemistries of these diseases tend to be rather similar. They include increased lactate production, diminished respiration and ATP production, and reflect the consequences of oxidative stress.
Accordingly, there is a need for therapeutic agents that are useful for the treatment or suppression of diseases associated with impaired mitochondria. There is also a need for agents that raise ATP levels and/or suppress oxidative stress and/or lipid peroxidation.